Fluoroacetates research

Difluoroacetic acid is much less toxic than fluoroacetic acid (LD q = 180 mg/kg mouse iv) (41). It is available in research quantities for about 5/g... 

Finally, recent developments on research into the first C-F bond forming enzyme are summarized. The fluorinase enzyme isolated from Streptomyces cat-tleya catalyzes the formation of 5 -fluoro-5 -deoxyadenosine from S-adenosyl-L-methionine and fluoride. The substrate specificity and subsequent transformation of the fluorinated nucleoside to fluoroacetic acid and to fluoro threonine are discussed. 

During the period of World War II, much research was undertaken, results of which were not published until 1947 and after, owing to questions of national security. In peurticular studies were made of fluorophosphidates [reviewed by Saunders (10)] and of derivatives of fluoroacetic acid and its higher homologues [reviewed by Pattison... 

The biochemical mechanism of the toxicity of fluoroacetate in mammals was first elucidated by the notable researches of the late Sir Rudolph Peters, who showed that in liver and kidney, the compound was metabolically transformed into an even more toxic fluorocitric acid isomer, a powerful inhibitor of the tricarboxylic acid cycle. These results together with those of others, Li ecq, Bergmann,... 

This topic will be only briefly highlighted here as synthetic biology (SB) is the topic of the previous chapter (Chapter 14) in this edition. Amyris and Sanofi have commercialised a semi-synthetic artemisinic acid process to enable the cost-effective production of artemisinin, a key API for antimalarial combination therapies, by inserting the artemisininic acid pathway into S. cerevisiae For discovery research, SB is starting to provide exciting new pathways into unique and novel secondary metabolites as possible new drugs or lead compounds for semi-synthetics. Walker et al. have demonstrated the ability of two polyketide synthase systems to accept fluoroacetate in place of acetate leading to the production of a number of novel... 

Fluoroacetate intoxication offers new possibilities to research. If a drug, a pathological condition or even a physical agent such as ionizing radiation do not decrease citrate accumulation in a rat after fluoroacetate poisoning, this means that they do not affect the utilization of glucose before aconitase action. If they do, one must look for a block somewhere between glucose and citric add. 

Goncharov, N.V., Jenkins, R.O., Radilov, A.S., 2006. Toxicology of fluoroacetate a review, with possible directions for therapy research. J. Appl. Toxicol. 26, 148-1161. 

DPC 961 (134, Scheme 2.21) has shown activity against wild-type HIV-1 and various non-nucleoside reverse transcriptase inhibitor-resistant HIV strains, and with greater potency than the structurally related efavirenz (Sustiva Bristol-Myers Squibb), an approved drug for HIV treat-ment. ° To facilitate the development of DPC 961, researchers at DuPont Pharmaceuticals Company (Wilmington, DE) developed an asymmetric conjugate addition strategy to introduce the trifluoromethyl amine stereocenter. As depicted in Scheme 2.21, treatment of the known aniline 128 ° with two equivalents of (R)-(-l-)-a-methylbenzyl isocyanate 129 afforded the hemiami-nal 130, which was subsequently converted into the 2(3//)-quinazolinone 131 by reaction with thionyl chloride and triethylamine. Reaction of the quinazolinone 131 with excess cyclopropylacetylene magnesium chloride 132 provided the dihydroquinazolinone 133 in 86% yield and 92% diastereomeric excess. Conversion of the dihydroquinazolinone 133 into DPC 961 134 involved treatment with tri-fluoroacetic acid or warm formic acid. Overall, this process provided 16 kg of DPC 961 134 in >55% overall yield from aniline 128. 

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